Polymeric delivery formulations of leuprolide with improved efficacy

Abstract

The present invention is directed to a flowable composition that is suitable for use as a controlled release implant. The flowable composition includes a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid. The flowable composition also includes a biocompatible polar aprotic solvent. The biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid. The flowable composition also includes leuprolide acetate.

1 - 46 . (canceled) 
     
     
         47 . A flowable composition suitable for use to form an in situ, single body controlled release implant, the composition comprising a non-aqueous, liquid solution of: (a) a biodegradable thermoplastic chain extended copolymer of lactide and glycolide including hexane diol as a chain extender; (b) N-methyl-2-pyrrolidone; and (c) leuprolide acetate; wherein,
 the copolymer has a weight average molecular weight of about 15,000 to about 45,000, and is present in the composition at about 30 wt % to about 50 wt %;   the N-methyl-2-pyrrolidone is present in the composition at about 45 wt % to about 70 wt %; and,   the leuprolide acetate is present in the composition at least at about 2 wt %.   
     
     
         48 . A flowable composition according to  claim 47  wherein the leuprolide acetate is present in the composition in an amount sufficient to reduce serum testosterone levels in a male patient. 
     
     
         49 . a flowable composition according to  claim 47  wherein the leuprolide acetate is present in the composition at about 2 wt % to about 8 wt %. 
     
     
         50 . A flowable composition according to  claim 47  wherein the sum of the weight percentages of the copolymer, N-methyl-2-pyrrolidone and leuprolide acetate is about 100%. 
     
     
         51 . A flowable composition according to  claim 49  wherein the sum of the weight percentages of the copolymer, N-methyl-2-pyrrolidone and leuprolide acetate is about 100%. 
     
     
         52 . A flowable composition according to  claim 47  wherein the composition is formulated for administration to a male patient about once per three months, once per four months or once per six months and produces in situ the single body implant. 
     
     
         53 . A flowable composition according to  claim 52  wherein the in situ implant reduces serum testosterone levels in the male patient. 
     
     
         54 . A biodegradable implant formed in situ, in a male patient, by the steps comprising: (a) injecting about 0.2 to about 0.5 ml of the flowable composition of  claim 47  within the body of the patient; and (b) allowing the N-methyl-2-pyrrolidone to dissipate to produce a solid, monolithic biodegradable implant of a microporous matrix of a core surrounded by a skin. 
     
     
         55 . A method of reducing serum testosterone levels in a male human comprising injecting subcutaneously into the male human about 0.2 ml to about 0.5 ml of a flowable composition comprising a non-aqueous, liquid solution of: (a) a biodegradable thermoplastic chain extended copolymer of lactide and glycolide including hexane diol as the chain extender; (b) N-methyl-2-pyrrolidone; and (c) leuprolide acetate; wherein
 the chain extended copolymer has a weight average molecular weight of about 15,000 to about 45,000 and is present in the composition at about 30 wt % to about 50 wt %;   the N-methyl-2-pyrrolidone is present in the composition at about 45 wt % to about 70 wt %; and,   the leuprolide acetate is present in the composition at least at about 2 wt %;   the flowable composition forms in situ a monolithic solid implant of a microporous matrix of a core surrounded by a skin within a body tissue of the male human.   
     
     
         56 . A method according to  claim 55  wherein the leuprolide acetate is present in the composition in an amount sufficient to reduce serum testosterone levels in a the male human; 
     
     
         57 . A method according to  claim 55  wherein the leuprolide acetate is present in the composition at about 2 wt % to about 8 wt %. 
     
     
         58 . A method according to  claim 55  wherein the solid implant is formed by diffusion of the N-methyl-2-pyrrolidone into the body fluid of the male human and precipitation of the chain extended copolymer. 
     
     
         59 . A flowable composition according to  claim 47  wherein the leuprolide acetate is present in the composition in an amount sufficient to reduce LHRH levels in a human.